Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rats and mice these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly however, the humanized CD28 superagonist TGN1412 caused severe and life threatening side effects during a recently conducted phase I clinical trail. The molecular mechanisms underlying the side effects of TGN1412 are as yet unclear.
During my talk I present data showing that TGN1412 as well as the commercially available CD28 superagonist ANCD28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T-cells but not in cynomolgus T-lymphocytes. The sustained Ca^++ -signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-gamma and TNF-alpha.
Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K appear to be absolutely required for CD28SA-mediated production of IFNgamma, IL2 and IL-10. Collectively, the data suggest a molecular basis for the unexpected side effects of TGN1412 and impinge on the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells.
Burkhart Schraven (*1958 in Hildesheim) is Professor of Immunology and Director of the Institute of Immunology at the Otto-von-Guericke-University in Magdeburg. He is speaker and coordinator of the Research Center “Immunologie“ Magdeburg-Halle (FZI) and member of the advisory board of the German Society of Immunology (DGFI). The main fields of research of Professor Schraven are alterations of immunological processes and signalling networks within the immune system.
Moderation: Professor Dr. Barbara M. Bröker